VEGF up-regulation by G93A superoxide dismutase and the role of malate-aspartate shuttle inhibition

Yael Mali, Nava Zisapel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

A gain of interaction of the amyotrophic lateral sclerosis (ALS)-linked G93A-superoxide dismutase-1 (G93A-hSOD1) with cytosolic malate dehydrogenase (cytMDH), a key enzyme in the malate-aspartate shuttle, diverts neurons towards anaerobic metabolism. Changes in vascular endothelial growth factor (VEGF) are reported in ALS and hypoxia. Here we report that expression of G93A-hSOD1 fused with green fluorescent protein in NSC-34 cells enhanced VEGF expression and levels of VEGF and its upstream regulator hypoxia-inducible factor (HIF-1α). G93A-hSOD1 expressing cells were unable to further up-regulated VEGF in response to Co2+ and H2O2. Amino-oxyacetate that inhibits the malate-aspartate shuttle caused a similar increase in VEGF mRNA and impaired response to H2O2 in WT-hSOD1 expressing cells. Interruption of the G93A-hSOD1/cytMDH interaction reduced VEGF expression in G93A-hSOD1 expressing cells and restored their ability to up-regulate VEGF in response to Co2+ and H2O2. These results demonstrate that the ALS-linked G93A hSOD1 mutation impairs VEGF regulation compatible with the inhibition of neuronal malate-aspartate shuttle.

Original languageEnglish
Pages (from-to)673-681
Number of pages9
JournalNeurobiology of Disease
Volume37
Issue number3
DOIs
StatePublished - Mar 2010

Funding

FundersFunder number
ISF Morasha Research Foundation

    Keywords

    • ALS
    • Amyotrophic Lateral Sclerosis
    • HIF
    • Hypoxia
    • Malate-aspartate shuttle
    • SOD1
    • VEGF

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